Natural Suppression of Human Immunodeficiency Virus Type 1 Replication Is Mediated by Transitional Memory CD8⁺T Cells

Abstract

HIV replication is suppressed in vitro by a CD8 + cell noncytotoxic antiviral response (CNAR). This activity directly correlates with an asymptomatic clinical state. The objective of this study was to identify the phenotype of CD8 + cell subsets having strong CNAR activity. CD8 + cell subset frequencies and CNAR levels were measured for human immunodeficiency virus (HIV)-uninfected individuals and three groups of HIV type 1 (HIV-1)-infected individuals: asymptomatic individuals with low-level viremia (vHIV), antiretroviral-drug-treated subjects with undetectable virus levels (TxHIV), and therapy-naïve aviremic elite controllers (EC). CD8 + cells from the vHIV individuals exhibited the highest HIV-suppressing activity and had elevated frequencies of CD45RA − CD27 + and PD-1 + (CD279 + ) cells. Functional assessments of CD8 + cells sorted into distinct subsets established that maximal CNAR activity was mediated by CD45RA − CCR7 − CD27 + and PD-1 + CD8 + cells. T cell receptor (TCR) repertoire profiles of CD8 + cell subsets having strong CNAR activity exhibited increased perturbations in comparison to those of inactive subsets. Together, these studies suggest that CNAR is driven by HIV replication and that this antiviral activity is associated with oligoclonally expanded activated CD8 + cells expressing PD-1 and having a transitional memory cell phenotype. The findings better describe the identity of CD8 + cells showing CNAR and should facilitate the evaluation of this important immune response in studies of HIV pathogenesis, resistance to infection, and vaccine development.

Inhibitory Potential of Subpopulations of CD8+T Cells in HIV-1-Infected Elite Suppressors

“…It should be noted that we used a conservative sorting scheme that did not account for all CD8 ϩ T cells, and recent studies have suggested that CD8 ϩ T cells with HIV-1-inhibitory activity may have phenotypes different from those described here (18,28). Functional studies of virus-specific CD8 ϩ T cells have shown that the markers used in this study also do not perfectly distinguish between central and effector memory CD8 ϩ T cells, and there is some plasticity in the expression of surface markers depending on the activation state (15,26,39,52,(54)(55)(56).…”

Initial HIV-1 Antigen-Specific CD8 + T Cells in Acute HIV-1 Infection Inhibit Transmitted/Founder Virus Replication

“…Cell surface expression of CD107a is associated with the capacity of antigen-specific CD8 ϩ T cells to eliminate infected cells and to inhibit HIV-1 replication. Phenotypic markers denoting transitional memory cells are also associated with the ability to inhibit HIV-1 replication (18,30). Furthermore, the characterization of the cytokine profile of CD8 ϩ T cells has identified MIP-1␤ as a correlate of virus control (16) and virus inhibition (18).…”

HIV/AIDS: 30 Years of progress and future challenges

“…Because CNAR appears during early primary infection and suppresses all HIV-1 and HIV-2 isolates via secretion of CAF, it has features of an innate immune response [44,45]. Healthy asymptomatic individuals, particularly LTSs, exhibit increased frequencies of the CD8 1 cells that mediate CNAR in comparison to those who progress to AIDS [46,47]. Moreover, studies of SIV-infected rhesus monkeys depleted of CD8 1 cells in vivo suggest that the virus level is maintained by a CD8 1 cell noncytotoxic process [48,49].…”

“…Another finding is that HIV-specific CTLs are often functionally immature [64] or exhausted and are therefore unable to respond appropriately to their cognate antigens [65]. However, these cells may exhibit CNAR [47]. Observations of HIV-specific CTL responses in HIV-exposed uninfected individuals [66] have given some credibility to the concept of a vaccine that elicits protective CTL activity.…”